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Molecular Brain
Published in: Molecular Brain 1/2016

Open Access 01-12-2016 | Research

Diversification of behavior and postsynaptic properties by netrin-G presynaptic adhesion family proteins

Authors: Qi Zhang, Hiromichi Goto, Sachiko Akiyoshi-Nishimura, Pavel Prosselkov, Chie Sano, Hiroshi Matsukawa, Kunio Yaguchi, Toshiaki Nakashiba, Shigeyoshi Itohara

Published in: Molecular Brain | Issue 1/2016

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Abstract

Background

Vertebrate-specific neuronal genes are expected to play a critical role in the diversification and evolution of higher brain functions. Among them, the glycosylphosphatidylinositol (GPI)-anchored netrin-G subfamily members in the UNC6/netrin family are unique in their differential expression patterns in many neuronal circuits, and differential binding ability to their cognate homologous post-synaptic receptors.

Results

To gain insight into the roles of these genes in higher brain functions, we performed comprehensive behavioral batteries using netrin-G knockout mice. We found that two netrin-G paralogs that recently diverged in evolution, netrin-G1 and netrin-G2 (gene symbols: Ntng1 and Ntng2, respectively), were responsible for complementary behavioral functions. Netrin-G2, but not netrin-G1, encoded demanding sensorimotor functions. Both paralogs were responsible for complex vertebrate-specific cognitive functions and fine-scale regulation of basic adaptive behaviors conserved between invertebrates and vertebrates, such as spatial reference and working memory, attention, impulsivity and anxiety etc. Remarkably, netrin-G1 and netrin-G2 encoded a genetic “division of labor” in behavioral regulation, selectively mediating different tasks or even different details of the same task. At the cellular level, netrin-G1 and netrin-G2 differentially regulated the sub-synaptic localization of their cognate receptors and differentiated the properties of postsynaptic scaffold proteins in complementary neural pathways.

Conclusions

Pre-synaptic netrin-G1 and netrin-G2 diversify the complexity of vertebrate behaviors and differentially regulate post-synaptic properties. Our findings constitute the first genetic analysis of the behavioral and synaptic diversification roles of a vertebrate GPI protein and presynaptic adhesion molecule family.
Literature
1.
Brown D, Waneck GL. Glycosyl-phosphatidylinositol-anchored membrane proteins. J Am Soc Nephrol. 1992;3:895–906.PubMed
2.
Ikezawa H. Glycosylphosphatidylinositol (GPI)-anchored proteins. Biol Pharm Bull. 2002;25:409–17.PubMedCrossRef
3.
Taylor DR, Hooper NM. GPI-anchored proteins in health and disease. In Post-translational modifications in health and disease. Volume 13 of the series of Protein Reviews. Edited by Vidal CJ: New York: Springer Science + Business Media; 2011. p. 39–55.
4.
Mani A, Singh S, Dwivedi M, Tripathi V, Gupta DK. An evolutionary account of GPI anchored proteins. Eur J Exp Biol. 2011;1:148–55.
5.
Walsh FS, Doherty P. Glycosylphosphatidylinositol anchored recognition molecules that function in axonal fasciculation, growth and guidance in the nervous system. Cell Biol Int Rep. 1991;15:1151–66.PubMedCrossRef
6.
Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science. 2000;289:1360–5.PubMedCrossRef
7.
Karagogeos D. Neural GPI-anchored cell adhesion molecules. Front Biosci. 2003;1:s1304–1320.CrossRef
8.
Labasque M, Faivre-Sarrailh C. GPI-anchored proteins at the node of Ranvier. FEBS Lett. 2010;584:1787–92.PubMedCrossRef
9.
10.
Brennaman LH, Zhang X, Guan H, Triplett JW, Brown A, Demyanenko GP, et al. Polysialylated NCAM and ephrinA/EphA regulate synaptic development of GABAergic interneurons in prefrontal cortex. Cereb Cortex. 2013;23:162–77.PubMedPubMedCentralCrossRef
11.
Nosten-Bertrand M, Errington ML, Murphy KP, Tokugawa Y, Barboni E, Kozlova E, et al. Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature. 1996;379:826–9.PubMedCrossRef
12.
Murai KK, Misner D, Ranscht B. Contactin supports synaptic plasticity associated with hippocampal long-term depression but not potentiation. Curr Biol. 2002;12:181–90.PubMedCrossRef
13.
Innos J, Philips MA, Leidmaa E, Heinla I, Raud S, Reemann P, et al. Lower anxiety and a decrease in agonistic behaviour in Lsamp-deficient mice. Behav Brain Res. 2011;217:21–31.PubMedCrossRef
14.
15.
Nithianantharajah J, Komiyama NH, McKechanie A, Johnstone M, Blackwood DH, St Clair D, et al. Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nat Neurosci. 2013;16:16–24.PubMedPubMedCentralCrossRef
16.
Ryan TJ, Kopanitsa MV, Indersmitten T, Nithianantharajah J, Afinowi NO, Pettit C, et al. Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior. Nat Neurosci. 2013;16:25–32.PubMedPubMedCentralCrossRef
17.
Nakashiba T, Ikeda T, Nishimura S, Tashiro K, Honjo T, Culotti JG, et al. Netrin-G1: a novel glycosyl phosphatidylinositol-linked mammalian netrin that is functionally divergent from classical netrins. J Neurosci. 2000;20:6540–50.PubMed
18.
Nakashiba T, Nishimura S, Ikeda T, Itohara S. Complementary expression and neurite outgrowth activity of netrin-G subfamily members. Mech Dev. 2002;111:47–60.PubMedCrossRef
19.
Yin Y, Miner JH, Sanes JR. Laminets: laminin- and netrin-related genes expressed in distinct neuronal subsets. Mol Cell Neurosci. 2002;19:344–58.PubMedCrossRef
20.
21.
Braisted JE, Catalano SM, Stimac R, Kennedy TE, Tessier-Lavigne M, Shatz CJ, et al. Netrin-1 promotes thalamic axon growth and is required for proper development of the thalamocortical projection. J Neurosci. 2000;20:5792–801.PubMed
22.
Nishimura-Akiyoshi S, Niimi K, Nakashiba T, Itohara S. Axonal netrin-Gs transneuronally determine lamina-specific subdendritic segments. Proc Natl Acad Sci U S A. 2007;104:14801–6.PubMedPubMedCentralCrossRef
23.
Zhang W, Rajan I, Savelieva KV, Wang CY, Vogel P, Kelly M, et al. Netrin-G2 and netrin-G2 ligand are both required for normal auditory responsiveness. Genes Brain Behav. 2008;7:385–92.PubMedCrossRef
24.
Lin JC, Ho WH, Gurney A, Rosenthal A. The netrin-G1 ligand NGL-1 promotes the outgrowth of thalamocortical axons. Nat Neurosci. 2003;6:1270–6.PubMedCrossRef
25.
Kim S, Burette A, Chung HS, Kwon SK, Woo J, Lee HW, et al. NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation. Nat Neurosci. 2006;9:1294–301.PubMedCrossRef
26.
27.
Seiradake E, Coles CH, Perestenko PV, Harlos K, McIlhinney RA, Aricescu AR, et al. Structural basis for cell surface patterning through NetrinG-NGL interactions. EMBO J. 2011;30:4479–88.PubMedPubMedCentralCrossRef
28.
Fukasawa M, Aoki M, Yamada K, Iwayama-Shigeno Y, Takao H, Meerabux J, et al. Case-control association study of human netrin G1 gene in Japanese schizophrenia. J Med Dent Sci. 2004;51:121–8.PubMed
29.
Aoki-Suzuki M, Yamada K, Meerabux J, Iwayama-Shigeno Y, Ohba H, Iwamoto K, et al. A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia. Biol Psychiatry. 2005;57:382–93.PubMedCrossRef
30.
Bisgaard AM, Rasmussen LN, Moller HU, Kirchhoff M, Bryndorf T. Interstitial deletion of the short arm of chromosome 1 (1p13.1p21.1) in a girl with mental retardation, short stature and colobomata. Clin Dysmorphol. 2007;16:109–12.PubMedCrossRef
31.
Eastwood SL, Harrison PJ. Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder. Neuropsychopharmacology. 2008;33:933–45.PubMedPubMedCentralCrossRef
32.
Ohtsuki T, Horiuchi Y, Koga M, Ishiguro H, Inada T, Iwata N, et al. Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations. Neurosci Lett. 2008;435:194–7.PubMedCrossRef
33.
Yaguchi K, Nishimura-Akiyoshi S, Kuroki S, Onodera T, Itohara S. Identification of transcriptional regulatory elements for Ntng1 and Ntng2 genes in mice. Mol Brain. 2014;7:19.PubMedPubMedCentralCrossRef
34.
Matsukawa H, Akiyoshi-Nishimura S, Zhang Q, Lujan R, Yamaguchi K, Goto H, et al. Netrin-G/NGL Complexes Encode Functional Synaptic Diversification. J Neurosci. 2014;34:15779–92.PubMedCrossRef
35.
Glickfeld LL, Histed MH, Maunsell JH. Mouse primary visual cortex is used to detect both orientation and contrast changes. J Neurosci. 2013;33:19416–22.PubMedPubMedCentralCrossRef
36.
37.
Soto F, Watkins KL, Johnson RE, Schottler F, Kerschensteiner D. NGL-2 regulates pathway-specific neurite growth and lamination, synapse formation, and signal transmission in the retina. J Neurosci. 2013;33:11949–59.PubMedPubMedCentralCrossRef
38.
Henry KR. Auditory brainstem volume-conducted responses: origins in the laboratory mouse. J Am Aud Soc. 1979;4:173–8.PubMed
39.
Doya K. Complementary roles of basal ganglia and cerebellum in learning and motor control. Curr Opin Neurobiol. 2000;10:732–9.PubMedCrossRef
40.
41.
Coura RS, Cressant A, Xia J, de Chaumont F, Olivo-Marin JC, Pelloux Y, et al. Nonaggressive and adapted social cognition is controlled by the interplay between noradrenergic and nicotinic receptor mechanisms in the prefrontal cortex. FASEB J. 2013;27:4343–54.PubMedPubMedCentralCrossRef
42.
43.
Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297:681–3.PubMedCrossRef
44.
Dudchenko PA. An overview of the tasks used to test working memory in rodents. Neurosci Biobehav Rev. 2004;28:699–709.PubMedCrossRef
45.
Olton DS, Samuelson RJ. Remembrance of places passed - spatial memory in rats. J Exp Psych-Anim Behav Proc. 1976;2:97–116.CrossRef
46.
van Asselen M, Kessels RP, Neggers SF, Kappelle LJ, Frijns CJ, Postma A. Brain areas involved in spatial working memory. Neuropsychologia. 2006;44:1185–94.PubMedCrossRef
47.
Niewoehner B, Single FN, Hvalby Ø, Jensen V, Meyer zum Alten Borgloh S, Seeburg PH, et al. Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus. Eur J Neurosci. 2007;25:837–46.PubMedPubMedCentralCrossRef
48.
49.
Aspide R, Fresiello A, de Filippis G, Gironi Carnevale UA, Sadile AG. Non-selective attention in a rat model of hyperactivity and attention deficit: subchronic methylphenydate and nitric oxide synthesis inhibitor treatment. Neurosci Biobehav Rev. 2000;24:59–71.PubMedCrossRef
50.
Robbins TW. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl). 2002;163:362–80.CrossRef
51.
Kobayashi Y, Sano Y, Vannoni E, Goto H, Suzuki H, Oba A, et al. Genetic dissection of medial habenula-interpeduncular nucleus pathway function in mice. Front Behav Neurosci. 2013;7:17.PubMedPubMedCentralCrossRef
52.
Fineberg NA, Potenza MN, Chamberlain SR, Berlin HA, Menzies L, Bechara A, et al. Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology. 2010;35:591–604.PubMedPubMedCentralCrossRef
53.
Hollingsworth EB, McNeal ET, Burton JL, Williams RJ, Daly JW, Creveling CR. Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3':5'-monophosphate-generating systems, receptors, and enzymes. J Neurosci. 1985;5:2240–53.PubMed
54.
Ricciardi S, Ungaro F, Hambrock M, Rademacher N, Stefanelli G, Brambilla D, et al. CDKL5 ensures excitatory synapse stability by reinforcing NGL-1–PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nature Cell Biol. 2012;14:911–23.PubMedCrossRef
55.
Zhang Y, Matt L, Patriarchi T, Malik ZA, Chowdhury D, Park DK, et al. Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release. EMBO J. 2014;33:1341–53.PubMedPubMedCentral
56.
Augustine GJ, Santamaria F, Tanaka K. Local calcium signaling in neurons. Neuron. 2003;40:331–46.PubMedCrossRef
57.
Lee SJ, Escobedo-Lozoya Y, Szatmari EM, Yasuda R. Activation of CaMKII in single dendritic spines during long-term potentiation. Nature. 2009;458:299–304.PubMedPubMedCentralCrossRef
58.
Emes RD, Pocklington AJ, Anderson CN, Bayes A, Collins MO, Vickers CA, et al. Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nat Neurosci. 2008;11:799–806.PubMedPubMedCentralCrossRef
59.
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12:529–40.PubMedCrossRef
60.
Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature. 1995;373:151–5.PubMedCrossRef
61.
Kutsuwada T, Sakimura K, Manabe T, Takayama C, Katakura N, Kushiya E, et al. Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron. 1996;16:333–44.PubMedCrossRef
62.
Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, et al. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell. 1998;92:279–89.PubMedCrossRef
63.
Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, et al. Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies. J Neurosci. 2007;27:2673–82.PubMedPubMedCentralCrossRef
64.
Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42:1021–6.PubMedCrossRef
65.
Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature. 1998;396:433–9.PubMedCrossRef
66.
Carlisle HJ, Fink AE, Grant SG, O'Dell TJ. Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity. J Physiol. 2008;586:5885–900.PubMedPubMedCentralCrossRef
67.
Fremeau Jr RT, Kam K, Qureshi T, Johnson J, Copenhagen DR, Storm-Mathisen J, et al. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science. 2004;304:1815–9.PubMedCrossRef
68.
Fremeau Jr RT, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, et al. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron. 2001;31:247–60.PubMedCrossRef
69.
Fremeau Jr RT, Voglmaier S, Seal RP, Edwards RH. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 2004;27:98–103.PubMedCrossRef
70.
Crawley JN: What's wrong with my mouse?: behavioral phenotyping of transgenic and knockout mice. New Jersey: John Wiley & Sons; 2007.
71.
Prusky GT, Alam NM, Douglas RM. Enhancement of vision by monocular deprivation in adult mice. J Neurosci. 2006;26:11554–61.PubMedCrossRef
72.
Fox MW. The visual cliff test for the study of visual depth perception in the mouse. Anim Behav. 1965;13:232–3.PubMedCrossRef
73.
Kurt S, Groszer M, Fisher SE, Ehret G. Modified sound-evoked brainstem potentials in Foxp2 mutant mice. Brain Res. 2009;1289:30–6.PubMedCrossRef
74.
Koch M, Schnitzler HU. The acoustic startle response in rats--circuits mediating evocation, inhibition and potentiation. Behav Brain Res. 1997;89:35–49.PubMedCrossRef
75.
Shibuki K, Gomi H, Chen L, Bao S, Kim JJ, Wakatsuki H, et al. Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice. Neuron. 1996;16:587–99.PubMedCrossRef
76.
Bearzatto B, Servais L, Cheron G, Schiffmann SN. Age dependence of strain determinant on mice motor coordination. Brain Res. 2005;1039:37–42.PubMedCrossRef
77.
Sano Y, Ornthanalai VG, Yamada K, Homma C, Suzuki H, Suzuki T, et al. X11-like protein deficiency is associated with impaired conflict resolution in mice. J Neurosci. 2009;29:5884–96.PubMedCrossRef
78.
Dere E, Huston JP, De Souza Silva MA. The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev. 2007;31:673–704.PubMedCrossRef
79.
Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985;14:149–67.PubMedCrossRef
80.
Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977;266:730–2.PubMedCrossRef
81.
Araya R, Noguchi T, Yuhki M, Kitamura N, Higuchi M, Saido TC, et al. Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice. Neurobiol Dis. 2006;24:334–44.PubMedCrossRef
82.
Sarter M, Bodewitz G, Stephens DN. Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines. Psychopharmacology (Berl). 1988;94:491–5.CrossRef
83.
Tanaka M, Shih PY, Gomi H, Yoshida T, Nakai J, Ando R, et al. Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol Brain. 2013;6:6.PubMedPubMedCentralCrossRef
84.
Kim JJ, Rison RA, Fanselow MS. Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. Behav Neurosci. 1993;107:1093–8.PubMedCrossRef
85.
Lee K, Kobayashi Y, Seo H, Kwak JH, Masuda A, Lim CS, et al. Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility. Mol Brain. 2015;8:38.PubMedPubMedCentralCrossRef
86.
Floresco SB, Seamans JK, Phillips AG. Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay. J Neurosci. 1997;17:1880–90.PubMed
87.
Moore SW, Tessier-Lavigne M, Kennedy TE. Netrins and their receptors. Adv Exp Med Biol. 2007;621:17–31.PubMedCrossRef
Metadata
Title
Diversification of behavior and postsynaptic properties by netrin-G presynaptic adhesion family proteins
Authors
Qi Zhang
Hiromichi Goto
Sachiko Akiyoshi-Nishimura
Pavel Prosselkov
Chie Sano
Hiroshi Matsukawa
Kunio Yaguchi
Toshiaki Nakashiba
Shigeyoshi Itohara
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2016
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/s13041-016-0187-5

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